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Open Access Protocol

Treatment of scabies using a tea tree oil-

BMJ Open: first published as 10.1136/bmjopen-2017-018507 on 31 May 2018. Downloaded from http://bmjopen.bmj.com/ on 2 October 2018 by guest. Protected by copyright.
based gel formulation in Australian
Aboriginal children: protocol for a
randomised controlled trial
Jackson Thomas,1 Rachel Davey,1 Gregory M Peterson,2 Christine Carson,3,4
Shelley F Walton,5 Tim Spelman,6 Tom Calma,7 Pascale Dettwiller,8 Jacinta Tobin,9
Faye McMillan,10 Paul Collis,1 Mark Naunton,1 Sam Kosari,1 Julia K Christenson,1
Andrew Bartholomaeus,1 John McEwen,1 Peter Fitzpatrick,11 Kavya E Baby12

To cite: Thomas J, Davey R, Abstract


Peterson GM, et al. Treatment Strengths and limitations of this study
Introduction  In remote Aboriginal communities in
of scabies using a tea tree Australia, scabies affects 7 out of 10 children before their
oil-based gel formulation in ►► The study will be conducted in collaboration with a
first birthday. This is more than six times the rate seen
Australian Aboriginal children: community-controlled Aboriginal Medical Service,
in the rest of the developed world. Scabies infestation is
protocol for a randomised in a clinically and culturally sound way with gover-
controlled trial. BMJ Open frequently complicated by bacterial infection, leading to
nance and approvals by expert Aboriginal and Torres
2018;8:e018507. doi:10.1136/ the development of skin sores and other more serious
Strait Islander researchers and organisations.
bmjopen-2017-018507 consequences, such as septicaemia and chronic heart and
►► A range of outcomes will be monitored, including
kidney diseases. Tea tree oil (TTO) has been used as an
►► Prepublication history and clinical response, relief of symptoms, recurrence,
antimicrobial agent for several decades with proven clinical
additional material for this adverse effects, adherence to treatment and patient
efficacy. Preclinical investigations have demonstrated
paper are available online. To acceptability.
view these files, please visit superior scabicidal properties of TTO compared with widely ►► The educational and community support packages
the journal online (http://​dx.​doi.​ used scabicidal agents, such as permethrin 5% cream delivered to participating communities as part of this
org/​10.​1136/​bmjopen-​2017-​ and ivermectin. However, current data are insufficient study will facilitate the effective control of scabies
018507). to warrant a broad recommendation for its use for the and offer long-term benefits to the community.
management of scabies because previous studies were ►► This is a single-site study.
Received 4 July 2017 small or limited to in vitro observations.
Revised 31 October 2017 ►► Adherence to the treatment protocol may be subop-
Methods and analysis  A pragmatic first trial will timal in an Aboriginal community setting in remote
Accepted 8 November 2017
examine the clinical efficacy of a simple and low-cost TTO Australia; however, pragmatic strategies have been
treatment against paediatric scabies and the prevention incorporated in the study design to promote adher-
of associated secondary bacterial infections, with 1:1 ence and limit attrition.
randomisation of 200 participants (Aboriginal children,
aged 5–16 years and living in remote Australia) into active
control (permethrin 5% cream) and treatment (5% TTO Sarcoptes scabiei var. hominis. Worldwide, there
gel) groups. The primary outcome for the study is clinical are 300 million cases of scabies each year, and
cure (complete resolution). Secondary outcome measures the prevalence is as high as >60% in Aborig-
will include relief of symptoms, recurrence rate, adverse
inal children and about 25% in Aboriginal
effects, adherence to treatment regimen and patient
acceptability.
adults in Australia. This is more than six times
Ethics and dissemination  The project has received the rate seen in resource-poor communities
approvals from the University of Canberra Human worldwide but comparable with reported
Research Ethics Committee (HREC 16-133), Wurli- prevalence rates in Fiji.1–4 Scabies infestation
Wurlinjang Health Service Indigenous subcommittee and has a negative impact on the quality of life of
the Aboriginal Medical Services Alliance Northern Territory infected individuals, resulting in substantial
reference group. The results of this study will be published stigmatisation and ostracism.5 6
in core scientific publications, with extensive knowledge S. scabiei releases antigens into the outer
exchange activities with non-academic audiences skin layer, resulting in local inflammatory and
throughout the duration of the project. immune reactions, leading to severe itching
For numbered affiliations see
Trial registration  ACTRN12617000902392; Pre-results.
end of article. (pruritus) and skin abrasions.7 8 Breaks in
the epidermis serve as an entry point for
Correspondence to
Introduction bacteria, such as streptococci or staphylo-
Dr Jackson Thomas;
​Jackson.​Thomas@​canberra.​ Scabies is a contagious, parasitic skin disease cocci, and complement inhibitors released
edu.a​ u (dermatosis) caused by the acarine itch mite by scabies mites promote bacterial growth.

Thomas J, et al. BMJ Open 2018;8:e018507. doi:10.1136/bmjopen-2017-018507 1


Open Access

This, in turn, can give rise to serious secondary infec- TTO result largely from oxidised oil, due to elevated levels

BMJ Open: first published as 10.1136/bmjopen-2017-018507 on 31 May 2018. Downloaded from http://bmjopen.bmj.com/ on 2 October 2018 by guest. Protected by copyright.
tions.2 Superinfected lesions may develop into cellulitis or of peroxides and other TTO degradation products.24 In
impetigo and may contribute to abscess formation. The typical in-use conditions (amber glass bottle fitted with
sequelae predispose the individual to sepsis, and other child-resistant polypropylene caps away from heat source
serious consequences, such as chronic heart and kidney and light), unformulated, neat TTO will have no appre-
diseases.3 Australia’s Northern Territory has the highest ciable degradation for up to 12 months.22 24 Due to its high
documented incidence of rheumatic heart disease in the volatility, 90% of the TTO evaporates quickly from the skin
world. Both chronic heart and kidney diseases are signif- surface, minimising the potential for TTO components to
icant causes of premature mortality among Aboriginal travel into the deeper layers of the skin and to be absorbed
Australians, contributing to a considerable life expec- into the bloodstream. However, terpinen-4-ol, α-terpineol
tancy gap (10–17 years) between Aboriginal and non-Ab- and 1,8-cineole can penetrate the epidermal layer of the
original people.7 skin sufficiently to produce antimicrobial, anti-inflamma-
Most current scabicides are potentially hazardous and tory and potentially acaricidal effects.20 25
are associated with moderate to serious cutaneous and TTO has been shown to possess insecticidal, acaricidal
systemic side effects.3 9–13 The safety of ivermectin (the and repellent properties against a range of medical and
sole oral therapy against scabies) has not been adequately veterinary pests, such as house dust mites,26 Demodex
established in the elderly, in patients with impaired liver mites,27 28 swine mites29 30 and head lice.31 In vitro testing
function, in children aged <5 years or in pregnant women. of TTO against human scabies mites demonstrated a supe-
No currently available acaricides possess ovicidal, antibac- rior result (60 min median survival time with 5% TTO) in
terial, anti-inflammatory and/or antipruritic properties. comparison with standard treatments (150 min with iver-
They are all ineffective at preventing treatment relapse mectin 100 µg/g; 120 min with permethrin 5%).4 32 TTO
arising from newly hatched mites, inflammatory skin reac- has also been used as a regular adjunct treatment (Royal
tions due to mite antigens and pyodermal progression. Darwin Hospital, treatment protocol) in combination
Emerging resistance to existing scabies treatments with benzyl benzoate and oral ivermectin for the manage-
raises concerns regarding their continuing effective- ment of crusted scabies.4 33 Additional information on the
ness.1 14–17 In vitro sensitivity data for scabies mites over therapeutic potential of TTO for scabies can be found in
the last 10 years (Australian data) indicate that median a recent review.21 However, current data are insufficient
survival times after treatment with the leading acaricides, to warrant a broad recommendation for its use in the
ivermectin and permethrin, have increased twofold to management of scabies.
threefold. Furthermore, treatment failures resulting from The aim of this research is to determine the efficacy
drug resistance have been documented.14 15 and safety of a TTO gel formulation (5% v/w TTO)
In developed countries, scabies infestation affects indi- versus the active comparator permethrin cream (Lyclear,
viduals with both low and high income and social status. 5% w/w permethrin) in treating scabies infestation and
The disease can also represent an expensive burden preventing associated secondary bacterial infections in
for communities or institutions experiencing outbreaks Aboriginal children living in remote Australia. In this
(such as long-term care facilities, nursing homes, hospi- study, we will assess whether the promising in vitro find-
tals, schools and prisons).18 19 A low-cost, topical treatment ings with TTO translate into a meaningful clinical benefit
would be extremely valuable, especially in developing when it is used under ‘real-world’ conditions, particularly
countries with low incomes and overcrowding, where in young Aboriginal people living in rural and remote
tropical and subtropical climates may promote the occur- communities, where scabies is common and causes signif-
rence of scabies infestation.18 19 icant morbidity and mortality. If proven effective, this
These public health concerns clearly demonstrate the treatment would prevent many Aboriginal children from
need for further clinical studies into new antiscabietic needing hospitalisation due to scabies-driven compli-
agents. Tea tree oil (TTO) has shown promising results cations, resulting in far-reaching outcomes among the
as an acaricide in preliminary in vitro studies.1 4 The Aboriginal communities within Australia and among
therapeutic benefits of TTO-containing formulations afflicted children internationally.
for a range of dermatological conditions have been Hence, we propose to perform an international
investigated in several small clinical studies, with mixed first, investigator-initiated, independently sponsored,
results.20 21 There have been concerns regarding the sensi- randomised controlled trial (RCT) of a 5% v/w TTO gel
tisation potential of neat TTO; however, when the oil is formulation for the treatment of scabies in Aboriginal
formulated in a suitable pharmaceutical base (cream/ children. The idea of evaluating the safety and clinical
ointment/gel) containing concentrations ≤25%, the risk efficacy of TTO for the management of scabies in a RCT
of adverse skin reactions appears low.22 The potential is novel and represents the first comprehensive inves-
of TTO toxicity in children is yet to be evaluated exten- tigation of TTO for the management of scabies. While
sively. A recent randomised clinical trial found that TTO Aboriginal people are intended as the primary beneficia-
(75% v/v) was well tolerated in the 30-day treatment of the ries of the proposed research, the pattern of scabies is
viral infection molluscum contagiosum in children (mean analogous to that observed in resource-poor and under-
age 6.3±5.1 years).23 Irritation and sensitising potential of privileged communities globally.

2 Thomas J, et al. BMJ Open 2018;8:e018507. doi:10.1136/bmjopen-2017-018507


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Figure 1  Study flow diagram. TTO, tea tree oil.

Methods and analysis Study site and personnel


Study design The study will take place in Katherine, a remote town in
We intend to test the clinical efficacy of TTO to Australia’s Northern Territory. It will be performed in
treat scabies infestation in children in a RCT, using a collaboration with the Wurli-Wurlinjang Health Service
TTO-based 5% v/w gel similar to a TTO gel formulation (WWHS), a community-controlled Aboriginal medical
previously tested in a clinical trial for cold sores.34 The 5% service. This health service began in 1972 and, based on
TTO gel contains approximately 14% poloxamer 407 gel, conservative estimates, has about 6400 regular Aborig-
in addition to other excipients such as formulation stabi- inal clients. An additional 7000 Aboriginal people who
lisers and preservatives. Permethrin 5% cream has been live in over 25 remote Katherine region communities are
selected as the active comparator due to its current status counted as occasional clients.
as the standard recommended therapy to treat scabies We plan to employ Aboriginal people as research staff
in children (and adults) in Australia. The design of this to help run the study, in the course of which they will
parallel group, two-arm, comparator-controlled, investi- have an opportunity to acquire the skills required to
gator-blind, non-inferiority trial with 1:1 allocation ratio manage similar work in the future. All attempts will be
is summarised in figure 1. Recruitment will be staggered made to ensure that the study is explained and conducted
over 18 months (October 2017–April 2019) until 200 in a culturally appropriate manner. The study docu-
participants are recruited. Our reporting of the protocol ments will be translated into three locally spoken aborig-
conforms to the Standard Protocol Items: Recommen- inal languages: East Side/West Side Kriol, Warlpiri and
dations for Interventional Trials (SPIRIT) 2013 checklist Gurindji. All research staff are aware of the guidelines
(online supplementary table S1 (SPIRIT Checklist) and of Good Clinical Practice and recognise the importance
online supplementary table S2 (WHO Trial Registration of undertaking the study in a culturally appropriate way.
Data Set)). Non-Aboriginal research staff will complete cultural
The research methodology has been developed in awareness training and will have a strong understanding
consultation with, and is being implemented by, Aborig- that the research should not interfere with community
inal and non-Aboriginal health professionals. Exten- values.
sive community consultations occurred prior to the Potentially eligible participants will be seen by a team
study protocol development. Furthermore, the Aborig- of Wurli staff including Aboriginal health practitioners
inal subcommittee at the study site (the Wurli-Wurlin- (AHPs) and general practitioners (GPs). All involved
jang Aboriginal Community Health Service) and the staff will follow the Central Australian Rural Practitioners
Aboriginal Medical Services Alliance Northern Territory Association (CARPA) code of practice from the clinic
reference group were involved in developing the study manual for primary healthcare practitioners in remote
protocol and have endorsed the study. and Aboriginal health services in central and northern

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Open Access

Australia.35 Study participants will be screened for eligi- that could alter the picture of scabies; (7) the presence

BMJ Open: first published as 10.1136/bmjopen-2017-018507 on 31 May 2018. Downloaded from http://bmjopen.bmj.com/ on 2 October 2018 by guest. Protected by copyright.
bility by an AHP at the WWHS. Other study-related duties of a complicated secondary bacterial infection; or (8) a
performed by this AHP will include participant recruit- known history of allergy to any of the study medications
ment, obtaining consent, clinical assessment, participant (permethrin, TTO or other essential oils).
follow-up and site coordination, as well as coordination
with other members of the study team (including inter- Recruitment and enrolment
state stakeholders). The AHP will also collaborate with Recruitment and enrolment will occur at a single site.
two Aboriginal elders/local champions (members of Participants will be recruited by an AHP while attending
the Wurli-Wurlinjang board of directors) to undertake the WWHS clinic in Katherine. An outline of the recruit-
community engagement initiatives (extensive commu- ment and enrolment process and a participant-based
nity consultations to promote study participation). Study study timeline is given in figure 2.
recruitment and treatment will be overseen by a group of Eligible participants will be offered adequate oppor-
senior GPs at the WWHS. tunities to discuss the study with the AHP on duty.
The cultural integrity of the participant will be fully
Participants respected, and potential participants will not be
The study will be confined to patients aged between 5 coerced into participation. The medical care of poten-
and 16 years, whose legally responsible caregiver is willing tial participants will not be affected by their choice not
for their child to participate. While there is a particu- to participate or to discontinue participation. Every
larly high burden of scabies among children aged less effort will be made to ensure the potential participant
than 5 years, the safety of TTO in this age group has fully understands the content of the Participant Infor-
not been adequately established to include them in this mation Sheet (online supplementary appendix A3)
trial. Informed consent (online supplementary appendix and consent forms. Information sessions in the form of
A1) will be sought from caregivers during the recruit- short videos (video tutorials with voice-overs in Aborig-
ment process (prior to eligibility assessment or enrol- inal languages, if required) will be shown to the partic-
ment). Caregivers will be expected to comply with the ipants and caregivers before the start of treatment to
requirements of the protocol. This includes being able explain the nature of scabies, how it is transmitted from
and willing to be contacted by telephone after the initial person to person, how to prevent recurrence and how
assessment and being able to provide written informed to systematically wash their fomites (clothing, bedding
consent. Furthermore, the child’s assent to participate in or towels). The study team will also provide detailed
the trial will be confirmed verbally and, if aged ≥12 years, written instructions (with the aid of flip cards) when
the child will be asked for written assent (online supple- dispensing the scabies formulations for home applica-
mentary appendix A2). At the time of recruitment, the tion by parents/caregivers and household members.
legally responsible caregiver will be asked whether the
participating child will have access to regular shower facil- Randomisation, allocation concealment
ities during the treatment course (ie, days 1 and 8), and After confirmation that the eligibility criteria have been
the need for a whole-body shower before application of met, the AHP will allocate participants to either the
treatment medications will be explained. intervention or control group using a predetermined,
Participant inclusion criteria are (1) the presence of age-stratified sequential serial number. He or she will
typical scabietic lesions (eg, papules, nodules or vesicles) then open the matched, sequentially numbered opaque
at classical sites of predilection (specifically the following envelope containing the treatment allocation instruc-
15 sites: face, head, palms, interdigits, sides of fingers, tions. The allocation ratio will be 1:1 active comparator
upper and lower extremities, wrists, axilla, nipple, umbil- (permethrin):test treatment (TTO), and the allocation
ical area and/or lower abdomen, genitalia, inguinal, sequence and treatment allocations will be concealed
buttocks and back area); (2) the presence of classical from trial participants and clinical assessors (AHPs)
burrows on clinical examination; (3) nocturnal pruritus; throughout the study. The simple randomisation schedule
(4) a history of scabies among family members or similar will be computer generated, and the randomisation will
symptoms among household contacts; and (5) access to be kept secure (password protected) by an independent
shower facilities and a telephone. statistician (based at the University of Canberra) who is
Exclusion criteria are (1) treatment with any topical otherwise not part of the research team. The actual treat-
scabicidal therapy in the month before entry into the ment allocation will not be disclosed to the staff members
study; (2) use of any topical or systemic treatment in the responsible for patient care, treatment, evaluation and
week before entry; (3) confirmed or suspected immuno- follow-up or to the study monitors. The treatment alloca-
suppressive or immunodeficient conditions, including tion will be concealed in all participant documents.
HIV infection; (4) receipt of more than 2 weeks of immu-
nosuppressants or immune-modifying drugs (eg, prednis- Medications and treatment
olone >0.5 mg/kg/day) in the preceding 4 weeks; (5) the All treatments prescribed in connection with the study
presence of scabies with an atypical presentation, such as will be provided free of charge to the participants.
crusted scabies; (6) the presence of any other skin disease Scabies treatments for day 1 and day 8 will be provided

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Figure 2  Overview of the trial recruitment, treatment and assessment process. AE, adverse event; AHP, Aboriginal health
practitioner.

concurrently at the first visit in well-labelled containers. cleft, umbilicus, skin folds, palms and soles, and webs
Treatment will consist of application of the product by between fingers and toes. The area behind the ears will
the participant or caregiver wearing plastic gloves and be given special attention while avoiding eyes and the
a gown following CARPA guidelines. Participants will mouth. Participants and caregivers will be instructed to
be instructed to shower or bathe (with non-medicated clip the participant’s fingernails and toenails and apply
soap) and have their bed linen changed before applying the scabies formulations under nails. They will also be
the treatment. The scabies formulations will be applied instructed to put on clean clothing after applying the
to every square inch of skin, from the posterior ear folds treatment. Contaminated clothing and linens should be
down over the entire body. This includes the intergluteal washed in the hot cycle of a washing machine and dried in

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Open Access

the hot cycle of a dryer for 10–20 min or dried under hot the four visits, examination of the entire body surface will

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sunlight. If the trial medication is washed off during hand be performed. The sites of lesions will be recorded on
washing, toileting or perineal care, it must be reapplied. body diagram sheets, and lesions will be photographed
The scabies treatment formulations will be applied at using a standardised protocol.36 The notations of their
night after an evening shower/bath. In the case of the appearance and whether they are new lesions or resid-
test medication (5% v/w TTO gel), the treatment will uals of original lesions will be determined by comparison
be applied on day 1 and day 8 and left on the body for with the pretreatment digital photographs. The severity
8–12 hours each time. After this time, the children will of infestation will be graded based on the number of body
shower/bathe (with non-medicated soap and water) to sites showing typical scabietic lesions and recorded as
wash off the treatment. The comparator group medi- mild infestation (<6 sites affected), moderate infestation
cation (permethrin 5% cream, single application only) (6–10 sites) or severe infestation (>10 sites).37 The extent
will also be applied as directed above on day 1, followed of lesions on the entire body will be recorded as mild
by a placebo treatment (identical standard formulation (≤10 lesions), moderate (11–49 lesions) or severe (≥50
minus permethrin) on day 8. Participants will be advised lesions).38 39 Trial data collection forms can be obtained
not to use or mix any other scabies treatment with trial on request from the corresponding author.
medications. The primary outcome measure in this study is the clin-
Test formulations (5% v/w TTO gel in an aqueous ical cure of scabies at the end of the 30-day observation
base) will be prepared following WHO Good Manufac- period. Outcome assessments will be conducted by inves-
turing Practices (GM, IDT Australia, VIC), and all formu- tigators blinded to treatment allocation. The principal
lations will be supplied in appropriate child-safe medicine investigator or coinvestigators will assess cure by referring
containers, labelled with the child’s identifiers and to target site photographs and marked body diagrams
dosing (application) instructions. The trial medications after data collection is complete. Cure is defined as the
will be stored in the clinic imprest at WWHS, and their absence of new lesions, and all old lesions healed, on day
supply will be supervised by the AHP. A 4-week expiry date 30 (residual, dry, non-inflammatory papules will not be
will be set for all test formulations. On recruitment, the considered to be active).37 Treatment failure is defined
AHP will provide participants/caregivers (blinded) with as the presence of new or unhealed lesions on day 30 in
sealed medication packs of identical appearance. The a participant who was not considered to be cured on day
study participants and caregivers will be given additional 16.
personal protective equipment for direct patient care, The secondary outcomes that will be investigated in this
including disposable long-sleeved gowns and gloves, in study are the rate of scabies recurrence, relief of pruritus,
order to reduce the risk of transmission and prevent rein- pyodermal progression (development of secondary bacte-
festation. Participants will also be provided with a sealable rial infections), adherence to the treatment regimen, the
easily identifiable biohazard bag to dispose of gloves and frequency/severity of adverse events (AEs) and patient
gowns. They will be asked to return this bag to the clinic acceptability of the treatment. Recurrence rate (or rate
during their follow-up visits for safe disposal. Care and of scabies reinfestation) will be measured by determining
precautions will be exercised while dealing with partici- the number of participants who are completely clear at
pants to minimise transmission.35 day 16 and develop new lesions by day 30. Pruritus will
To further prevent the spread of scabies, all other family be evaluated using a 0–10 visual analogue scale, where
contacts will be provided therapy with a standard-ap- 0 represents ‘no itch’ and 10 represents ‘worst imagin-
proved scabicide (permethrin 5%). This will be provided able itch’. All participants will be followed up for 3 weeks
to caregivers in visually distinguishable containers with post-intervention to assess pruritus. Antipruritic medi-
clear instructions using coloured labels to prevent medi- cation, if needed, will be given after this period. The
cation errors. Crusted scabies-infested house contacts will proportion of children with secondary bacterial compli-
be identified by questioning parents/caregivers, and the cations will be determined by having trained AHPs iden-
AHP will alert the Northern Territory Centre for Disease tify and grade the severity of infected skin sores. Severity
Control for the appropriate public health response. will be stratified by researchers into mild impetigo (one
purulent or crusted sore and <5 sores in total) or severe
Follow-up and clinical assessment impetigo (two or more purulent or crusted sores or ≥5
After giving consent, the parent or caregiver attending sores in total).40 Participants’ acceptability of treatments
with the child will be asked a standard set of questions by will be assessed during the three follow-up visits by asking
the trained AHP to capture potentially important demo- participants and caregivers to rate the treatment in terms
graphic details. Clinical evaluations (blinded to treat- of effectiveness, side effects, convenience and overall
ment allocation) will be made by experienced clinical satisfaction.
investigators (trained AHP/Aboriginal nurse) following
CARPA guidelines. Adherence and retention
All participants will be followed up on days 9, 16 and Innovative strategies will be employed to motivate partic-
30 and will be thoroughly examined by the same clinical ipants’ adherence to the treatment protocol and to
staff member (AHP) as at baseline (day 1). At each of increase retention. These include providing each trial

6 Thomas J, et al. BMJ Open 2018;8:e018507. doi:10.1136/bmjopen-2017-018507


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participant with a tablet with preset reminder alarms and trial medication. AEs considered related to the trial medi-

BMJ Open: first published as 10.1136/bmjopen-2017-018507 on 31 May 2018. Downloaded from http://bmjopen.bmj.com/ on 2 October 2018 by guest. Protected by copyright.
preloaded engaging video tutorials in relevant Aborig- cation will be followed either until resolution or until the
inal languages to facilitate the correct and easy appli- event is considered stable. The following information will
cation of trial medications. Furthermore, gift vouchers be recorded where available: description, date of onset
(prepaid telephone cards and/or grocery vouchers) will and end date, severity, expectedness, assessment of relat-
be given to participants who attend all follow-up visits to edness to trial medication, other suspect drug or device,
compensate for participant transport to the study centre action taken and whether the participant is withdrawn
for assessments. A limited supply of washing powder, chil- due to AE.
drens clothing and bed linen will be provided to study The investigator will use their clinical judgement to
participants to better control the scabies infestation in decide whether an AE is of sufficient severity to require
the local communities and to facilitate the accomplish- the discontinuation of the participant’s study medication.
ment of long-term treatment goals. A participant may also voluntarily withdraw from treat-
The AHP will review each participant by phone to record ment due to what he or she perceives as an intolerable
any apparent adverse effects and to monitor adherence to AE. If either of these occurs, the participant will undergo
the treatment protocol, such as washing of fomites and an end of trial assessment and be given appropriate care
permethrin use by other household members. Phone under medical supervision until symptoms cease or the
calls will be made daily for 3 days following each treat- condition becomes stable.
ment application and every 5th day post treatment phase
(figure 2). The participant/caregiver will also receive Feasibility
reminder SMS alerts in the afternoon on each treatment The Katherine region is a uniquely suitable site at which
day and the day before each follow-up assessment. In to perform this trial because of its proximity to Aboriginal
cases where telephone follow-up is not successful, the communities. The region is home to about 15 000 Aborig-
AHP will undertake healthcare home visits to enhance inal residents, 6400 of whom are regular clients at WWHS.
participants’ adherence to the treatment protocol and to Our team has already established a research collabora-
improve retention. tion and agreement with the recruitment site (WWHS)
Participant compliance to the treatment protocols will to recruit participants (n=200) within the proposed time-
be assessed objectively by weighing the tubes of medi- frame (18 months).
cations prior to the supply and at the end of treatment.
Parents/caregivers will be reminded by nursing staff to Sample size
return the formulations and tablets at the second assess- The study sample size was calculated based on previous
ment visit. At the completion of the trial, the tablet observational studies, in vitro data on TTO and the inves-
computers will be collected and donated to local schools tigators’ findings from similar trials.38 Calculations are
in the participating trial region for educational purposes. based on the assumptions that permethrin 5% cream
will have a 90% cure rate, and TTO 5% formulation will
Monitoring of AEs have an 80% cure rate at 15 days. Given an estimated
During each follow-up visit and telephone call, the partic- 10% difference in cure rate in favour of the comparator
ipants/caregivers will be asked about the occurrence of permethrin arm, a sample of 69 participants per arm
any solicited or unsolicited adverse reactions to the treat- (138 in total) is required to be 80% sure that the upper
ment. This will be done using a prespecified list of AEs limit of a one-sided 95% CI will exclude a difference in
including local adverse reactions (swelling, stinging/ favour of the permethrin arm of more than 25%, thus
burning, itching, induration, erythema, sore eyes or establishing non-inferiority between TTO and perme-
conjunctivitis) and systemic adverse reactions (fever, thrin. A larger sample would have permitted us to detect
nausea, vomiting, headache and dizziness). Medically a smaller non-inferior difference (eg, 15% and 10%).
significant AEs will be documented from randomisation However, it may not be practical to recruit a larger cohort
until the end of the study (day 30). without presenting preliminary clinical safety efficacy
The relationship between each AE and the trial medi- data, especially in children. The results will be considered
cation will be determined by a medical doctor according significant if P≤0.05. The current study will recruit 200
to the following definitions: (1) related: the AE follows participants (100 in each arm, to allow for up to 30% attri-
a reasonable temporal sequence from trial medication tion, based on our previous studies).
administration and it cannot reasonably be attributed
to any other cause; (2) not related: the AE is probably Statistical analysis
produced by the participant’s clinical state or by other Data will be reported in accordance with the Consol-
modes of therapy administered to the participant. All AEs idated Standards of Reporting Trials guidelines. A
that are observed by an investigator or member of the detailed analysis plan will be approved by all investiga-
healthcare team, that are reported by the participant (in tors prior to any data analysis. For each outcome, the
person or on the telephone) or that are recorded in the number of evaluable children in each treatment group
participant’s medical records will be detailed in the case will be presented, and data analysts will be blinded
report forms (CRFs), whether or not attributed to the to treatment allocation. Categorical variables will be

Thomas J, et al. BMJ Open 2018;8:e018507. doi:10.1136/bmjopen-2017-018507 7


Open Access

summarised using frequency and percentage. Contin- Premature termination of the study

BMJ Open: first published as 10.1136/bmjopen-2017-018507 on 31 May 2018. Downloaded from http://bmjopen.bmj.com/ on 2 October 2018 by guest. Protected by copyright.
uous variables will be first assessed for significant depar- This study can be terminated at any stage at the discre-
tures from normality using a Shapiro-Wilk test and tion of the trial sponsor (University of Canberra) or the
summarised using mean and SD or median and IQR principal investigator (JT) in consultation with the DSMC
as appropriate. Significantly skewed variables will be and CTM group. If the study is prematurely terminated,
further assessed for transformation and analysed para- the principal investigator will immediately inform current
metrically or non-parametrically, as appropriate. Differ- trial participants and notify the relevant ethics committee
ences in cure rate between treatment arms groups will be within 15 days.
presented with a corresponding 95% CI and one-sided An interim analysis will be conducted by an indepen-
P value. Kaplan-Meier estimates and a log-rank test will dent statistician after the 100th participant has reached
be used to compare time-to-event outcomes by treatment study day 30 to allow the DSMC to assess the ongoing
arm. Cox proportional hazards regression will be used appropriateness of the trial. The statistician will present
to adjust the association between treatment arm and the data to the DSMC in an interim report, including a
time-to-event outcomes for known or suspected baseline descriptive analysis of AEs considered related to study
confounders. The baseline comparability of groups will treatment, the number of deaths in each study group
be further assessed, using the centre as an adjustment (along with causality) and the number of participants
factor. Hazard proportionality will be assessed through experiencing each medically significant AE occurring in
analysis of scaled Schoenfeld residuals. the first 30 days of the study. The interim analysis will be
To reduce bias, all analyses will be based on an descriptive, and no hypothesis testing or presentation of
‘intention to treat’ approach; analyses will include all P values for group comparisons will be made. The results
randomised participants, whether treated or not, as well of the interim analysis will remain confidential and will
as any participants who have withdrawn prematurely or not be shared with study investigators unless the DSMC
are poorly compliant. An a priori subgroup analysis will feels it is necessary to do so.
be performed by age group (<12 years vs 12–16 years). A
test for interaction will be performed to evaluate differen- Ethical considerations
tial treatment effects by subgroup. Sensitivity analyses will While preclinical studies, including hospital and labo-
be conducted to compare: (1) the available data analysis ratory-based investigations, provide grounds to expect
with alternative assumptions about any missing data and a positive outcome for a TTO intervention, sufficient
(2) the 'treatment allocated' approach with 'treatment equilibrium exists to warrant an RCT of its use for scabies
received' approach. management in a community setting. Aboriginal liaison
workers will be sought to assist in participant recruitment.
Parental consent will be requested on the basis of a full
Study management explanation of known (or potential) risks and uncertainty
This study is being supported by funding provided of benefit. Participants will also be given the option to
through the University of Canberra Collaborative Indig- provide additional consent for their data to be used in
enous Research Initiative (​UC-​CIRI@​canberra.​edu.​au). future ancillary studies.
The proposed Clinical Trial Management (CTM) group The privacy of participants will be protected by appro-
will consist of the coinvestigators (including the trial stat- priate collection and storage of data. Participants will be
istician) and the data manager. They will hold budgeted identified only by initials and a participant ID number
bimonthly teleconferences to review the overall conduct on the CRFs and in any electronic databases. The data
of the study. The trial operations team will include the collection forms will be stored in locked filing cabinets
site coordinator and data manager. They will telecon- in a locked office at the participating clinic until the end
ference monthly to discuss operational issues including of the study period. All documents will only be acces-
data collection, cleaning and recruitment. Data will sible by trial staff and authorised personnel. Documents
be collected on the study-specific CRFs. All data will containing personal information will not be stored elec-
be entered onto the password-protected online data- tronically and will be anonymised as soon as it is practical
base provided by WebSpirit, stored at the University of to do so. Data collection forms will be held for at least 15
Canberra, Discipline of Pharmacy. All coinvestigators will years on University of Canberra servers, based on National
have access to the final trial dataset. Data queries will be Health and Medical Research Council guidelines. These
raised and data cleaned by the data manager/trial statis- will then be destroyed.
tician and site coordinators via WebSpirit. The indepen- Participants enrolled in the study will be covered
dent Data and Safety Monitoring Committee (DSMC) by the research sponsor (University of Canberra) for
will be chaired by an independent paediatric infectious indemnity and/or compensation for negligent harm
disease clinician and also include a pharmacist, a statisti- or non-negligent harm arising specifically from an acci-
cian and a representative from the Child Health Indige- dental injury and occurring as a consequence of the
nous Reference Group (WWHS). This committee will be research subject’s participation in the trial.
responsible for monitoring the safety of the trial and will A protocol amendment history will be maintained
meet approximately every 4 months. and updated as necessary throughout the trial (online

8 Thomas J, et al. BMJ Open 2018;8:e018507. doi:10.1136/bmjopen-2017-018507


Open Access

supplementary table S3). Independent audits of trial JKC, PD, PC, PF, KEB and JT designed the implementation aspects of this protocol.

BMJ Open: first published as 10.1136/bmjopen-2017-018507 on 31 May 2018. Downloaded from http://bmjopen.bmj.com/ on 2 October 2018 by guest. Protected by copyright.
conduct will be conducted annually by authorised All authors, including SK, participated in the preparation of the manuscript by
providing comments on drafts written by JT and approving the final version.
representatives from the sponsoring and/or host insti-
Funding  This work was supported by a grant received from University of Canberra
tutions. The processes audited will include participant
Collaborative Indigenous Research Initiative (2016-2018).
recruitment, enrolment, allocation and assessment;
Competing interests  None declared.
reporting of harms; completeness, accuracy and time-
liness of data collection; and adherence to the Inter- Patient consent  Caregiver consent obtained.
national Conference on Harmonisation Good Clinical Ethics approval  The study protocol, culturally appropriate information and consent
Practice guidelines. materials were reviewed and approved by the Indigenous staff at University of
Canberra (The Ngunnawal Centre), the University of Canberra Human Research
Ethics Committee (HREC 16-133), WWHS Indigenous subcommittee, study
Dissemination reference group and the reference group from AMSANT.
Research feedback at the end of the project will be in Provenance and peer review  Not commissioned; externally peer reviewed.
a form that is useful and understandable and include
Data sharing statement  The deidentified data will be made available in an open-
both a verbal and written summary detailing the input access repository after publishing the study results.
received and project outcomes. A suitably qualified
Open Access This is an Open Access article distributed in accordance with the
Aboriginal person will be employed to liaise between Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which
Aboriginal communities and the research team to permits others to distribute, remix, adapt, build upon this work non-commercially,
disseminate the study results and feedback to the local and license their derivative works on different terms, provided the original work is
communities at large. The results will also be provided properly cited and the use is non-commercial. See: http://​creativecommons.​org/​
licenses/​by-​nc/​4.​0/
to the council and relevant community organisations.
© Article author(s) (or their employer(s) unless otherwise stated in the text of the
The findings of this trial will be disseminated through article) 2018. All rights reserved. No commercial use is permitted unless otherwise
peer-reviewed journals and national and international expressly granted.
scientific meetings, as well as to the participating
communities. The Aboriginal reference group and the
study CTM group will monitor public dissemination of
any research findings. All reports will be submitted to References
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10 Thomas J, et al. BMJ Open 2018;8:e018507. doi:10.1136/bmjopen-2017-018507